tbuckley/cabot-search huggingface dataset:
Sintilimab plus bevacizumab as maintenance therapy for patients with unresectable hepatocellular carcinoma treated with transarterial chemoembolization: A phase Ib study.
Authors: Mingyue Cai, Wei Liang, Wensou Huang, Yongjian Guo, Licong Liang, Jingwen Zhou, Liteng Lin, Haihui Deng, Kangshun Zhu
Journal: Journal of Clinical Oncology (2022)

e16165 Background: Sintilimab (a PD-1 inhibitor) plus bevacizumab (Sin-Bev) has been demonstrated to confer a significant survival benefit over sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). This phase Ib study (NCT04592029) aimed to evaluate the safety and efficacy of Sin-Bev for patients with uHCC who received transarterial chemoembolization (TACE). Methods: The key eligibility criteria were: age ≥ 18 years; BCLC B/C stage uHCC; no prior systemic therapy and non-curative local treatments; Child-Pugh score ≤7; ECOG PS ≤1. This study included dose escalation and dose expansion stages. In the dose escalation stage, a 3+3 design was employed to determine the safety of a standard dose of sintilimab (200 mg Q3W) plus two possible doses of bevacizumab (group A: 7.5 mg/kg Q3W; group B: 15.0 mg/kg Q3W) after TACE. In the dose expansion stage, additional 30 patients were randomized 1:1 to each group. Sintilimab and bevacizumab was started at 3-7 days after the first TACE (TACE was repeated on demand). The primary endpoints were the incidence of adverse events (AEs) and progression free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: At the time of data cutoff (January 20th, 2022), 36 patients were enrolled (18 in each group). One patient in group A withdrew from the study after the first cycle of treatment. Of the remaining 35 patients, 20 (57.1%) had disease at BCLC C stage, 15 (42.9%) had macroscopic vascular invasion and 11 (31.4%) had extrahepatic metastasis. The mean largest tumor size was 10.5±5.2 cm. The median follow-up was 9.57 (range, 4.4-15.6) months. Thirty-one patients (86.1%, n=36) had treatment-related AEs (83.3% in group A vs. 88.9% in group B, P=1.000). All the AEs were mild (&lt;grade 2) and manageable. During follow-up, 19 patients (54.3%) experienced disease progression (per RECIST 1.1 or mRECIST). The median PFS was 7.2 (95% CI 3.6-10.8) months (6.7 [95% CI 4.7-8.8] months in group A vs. 8.4 [95% CI 3.9-12.8] months in group B, P=0.832). The median PFS in this report was immature due to some later enrolled patients were censored. Thus, it is likely to improve with longer follow-up. The ORR per RECIST 1.1 and mRECIST was 37.1% (41.2% in group A vs. 33.3% in group B, P=0.733) and 80.0% (88.2 in group A vs. 72.2% in group B, P=0.402), respectively. The DCR per RECIST 1.1 or mRECIST was 91.4% (94.1% in group A vs. 88.9% in group B, P=1.000). The median OS was not reached. Conclusions: Sin-Bev showed preliminary clinical benefits and an acceptable safety profile in uHCC patients treated with TACE. The study is still ongoing and further follow-up is required to obtain the final survival results. Clinical trial information: NCT04592029.
High pulsatile load ex vivo decreases arterial stiffness by altering the viscous, but not elastic, mechanical properties of the arterial wall
Authors: C Neutel, C Wesley, P Puylaert, GRY De Meyer, W Martinet, PJ Guns
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Research Foundation - Flanders (Brussels, BE): ==&amp;gt; [DUTCH]: "Fonds voor Wetenschappelijk Onderzoek (FWO) - Vlaanderen" Introduction The pulsatile character of blood flow in the central arteries results in a local transmission of energy to the arterial wall, acting on both the viscous and elastic components of the arterial wall. The amplitude of the "pulsatile load" is known to modulate the mechanosensitive properties of blood vessels. Purpose To evaluate the behavior of both the viscous and elastic components of the mouse aorta under altered pulsatile loading. Moreover, we aimed to assess regional differences in (arterial) tissue stiffness, as well as the contribution of vascular smooth muscle cell (VSMC) contractility under altered pulsatile conditions. Methods Aortic segments from C57Bl6 (n=9) mice were mounted in a Rodent Oscillatory Set-up for Arterial Compliance (ROTSAC), and subjected to high frequency (10 Hz) cyclic stretch at alternating loads (i.e. 20 to 100 mmHg with mean pressures ranging from 80 to 200 mmHg). Diastolic and systolic diameter, compliance, and the Peterson elastic modulus (Ep), as a measure of aortic stiffness, were determined. Viscous modulus (EV) was extracted from pressure-diameter tracings by eliminating loop hysteresis. Afterwards, the elastic modulus (EE) was calculated as the slope of the resulting pressure-diameter tracing: (P_elastic)= (P_total) - (EV * (dD/dt)) To assess regional differences in response to changes in pulsatile load, the most proximal aortic region (i.e., thoracic ascending aorta) was compared to a more distal aortic region (i.e., abdominal infrarenal aorta). Results Increasing pulse pressure from 40 to 100 mmHg decreased arterial stiffness (298 ± 9 vs. 270 ± 9 mmHg; p &amp;lt; 0.0001). Analyzing viscoelasticity revealed that increasing pulsatile load from 40 to 100 mmHg decreased EV (0.24 ± 0.02 vs. 0.21 ± 0.02 mmHg.s/mm; p &amp;lt; 0.01) but not EE. 50 mM KCl-induced VSMC contraction increased vessel stiffness (298 ± 9 mmHg vs. 395 ± 12 mmHg; p &amp;lt; 0.0001). This effect was pronounced at low pulse pressures (20 and 40 mmHg) while at higher pulse pressures (60, 80 and 100 mmHg) contraction-induced stiffness did not occur. Interestingly, the distal region of the aorta was stiffer than the proximal region (367 ± 60 vs. 289 ± 36 mmHg; p &amp;lt; 0.01) and had a higher EV (0.77 ± 0.2 vs. 0.21 ± 0.05 mmHg.s/mm; p &amp;lt; 0.0001). Increasing pulsatile load from 40 to 100 mmHg decreased the EV from distal aortic tissue more than the EV of tissue from the proximal region (-0.26 ± 0.02 vs. -0.06 ± 0.007 mmHg.s/mm). Conclusion High pulsatile load decreased arterial stiffness by decreasing the viscous mechanical properties. This effect was more pronounced in the distal region of the aorta.
RACE IT - A prospective, single arm, multicenter, phase II-trial to assess safety and efficacy of preoperative RAdiation therapy before radical CystEctomy combined with ImmunoTherapy in locally advanced urothelial carcinoma of the bladder (AB 65/18)
Authors: S.C. Schmid, K. Schiller, A.K. Seitz, F.J. Koll, F. Beckert, P. Korn, J. Lewerich, P. Maisch, A. Sauter, C. Rödel, M. Flentje, T. Riedel, S. Combs, F. Zengerling, C. Bolenz, H. Kübler, J.E. Gschwend, M. Retz
Journal: European Urology (2022)
Multistate Outbreak of <i>Listeria monocytogenes</i> Infections Linked to Fresh, Soft Hispanic-Style Cheese — United States, 2021
Authors: Alexandra Palacios, Mark Otto, Eileen Flaherty, Michelle M. Boyle, Lenka Malec, Kelsey Holloman, Mabel Low, Allison Wellman, Corinne Newhart, Lauren Gollarza, Tracey Weeks, Anthony Muyombwe, Kristen Lozinak, Erin Kafka, Daniel O'Halloran, Teresa Rozza, David Nicholas, Stranjae Ivory, Katherine Kreil, Jasmine Huffman, Laura Gieraltowski, Amanda Conrad
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Listeriosis is a serious infection usually caused by eating food contaminated with the bacterium Listeria monocytogenes. An estimated 1,600 persons become ill with listeriosis each year, among whom approximately 260 die. Persons at higher risk for listeriosis include pregnant persons and their newborns, adults aged ≥65 years, and persons with weakened immune systems. Persons with invasive listeriosis usually report symptoms starting 1-4 weeks after eating food contaminated with L. monocytogenes; however, some persons who become infected have reported symptoms starting as late as 70 days after exposure or as early as the same day of exposure (1). On January 29, 2021, PulseNet, the national molecular subtyping surveillance network coordinated by CDC, identified a multistate cluster of three L. monocytogenes infections: two from Maryland and one from Connecticut (2). CDC, the Food and Drug Administration (FDA), and state and local partners began an investigation on February 1, 2021. A total of 13 outbreak-related cases were eventually identified from four states. All patients reported Hispanic ethnicity; 12 patients were hospitalized, and one died. Rapid food testing and record collection by regulatory agencies enabled investigators to identify a brand of queso fresco made with pasteurized milk as the likely source of the outbreak, leading to an initial product recall on February 19, 2021. Fresh, soft Hispanic-style cheeses made with pasteurized milk are a well-documented source of listeriosis outbreaks. These cheeses can be contaminated with L. monocytogenes unless stringent hygienic controls are implemented, and the processing environment is monitored for contamination (3). U.S. public health agencies should establish or improve communications, including new methods of disseminating information that also effectively reach Hispanic populations, to emphasize the risk from eating fresh, soft Hispanic-style cheeses, even those made with pasteurized milk.
Birtamimab in patients with Mayo stage IV AL amyloidosis: Rationale for confirmatory affirm-AL phase 3 study.
Authors: Morie A. Gertz, Vaishali Sanchorawala, Ashutosh D. Wechalekar, Yukio Ando, Youngil Koh, Christie Nie, Xiaohua Sheng, Ansgar Conrad, Efstathios Kastritis
Journal: Journal of Clinical Oncology (2022)

TPS8076 Background: Light chain (AL) amyloidosis is a progressive and typically fatal disorder caused by misfolded AL protein produced by plasma cells. Birtamimab is a monoclonal antibody designed to neutralize circulating soluble and deposited insoluble amyloid, thus promoting phagocytic clearance. In 2018, the phase 3 VITAL study in newly diagnosed, treatment-naive patients was terminated based on futility analysis of the primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization &gt; 90 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over placebo + SOC (0.835 [95% CI: 0.5799, 1.2011]; p = 0.330). Post-hoc analysis of ACM over 9 months revealed a substantial survival benefit (HR = 0.413 [95% CI: 0.191, 0.895]; p = 0.025) in patients at high risk for early death (Mayo Stage IV). Post-hoc analyses of secondary endpoints in this subgroup indicated meaningful improvements in health-related quality of life (assessed with 36-Item Short Form Health Survey version 2; SF-36v2) and 6-minute walk test (6MWT) distance with birtamimab + SOC (p &lt; 0.05) at 9 months. Methods: The phase 3, double-blind, placebo-controlled AFFIRM-AL study (NCT04973137) will enroll up to 150 Mayo Stage IV patients with newly diagnosed, untreated AL amyloidosis. Patients will be randomized (2:1) to 24 mg/kg intravenous birtamimab or placebo every 28 days. Both arms will receive concomitant chemotherapy with a first-line bortezomib-containing regimen, with or without daratumumab (D), at the discretion of the investigator. Patients will be stratified at randomization based on their 6MWT distance ( &lt; 300 vs ≥300 meters) and initiation of D. The primary efficacy endpoint is time to ACM. Secondary endpoints are change from baseline to month 9 in the physical component summary of the SF-36v2 and 6MWT distance. This trial is powered at a significance level of 0.1 under a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA). Given the &gt; 50% relative risk reduction for ACM observed in the post-hoc analysis of VITAL for patients with Mayo Stage IV disease, the AFFIRM-AL study is designed to confirm this effect of birtamimab. Approximately 130 global sites are planned; site initiation and patient randomization are underway. Conclusion: Treatments that improve survival in AL amyloidosis are needed, particularly for patients with advanced cardiac involvement, as median overall survival for those with Mayo Stage IV disease is ̃6–9 months. The AFFIRM-AL study is designed to confirm the survival benefit observed in the VITAL study in patients with Mayo Stage IV AL amyloidosis. Clinical trial information: NCT04973137.
Transplant renal artery stenosis: Study of incidence using doppler ultrasound, risk factors and analysis effect in graft outcomes
Authors: C. Calzas Montalvo, J. Medina Polo, N.R. Miranda Utrera, M.P. Caro González, R. Santos Perez De La Blanca, M. Hernandez Arroyo, E. Peña Vallejo, J. Teigell Tobar, S. Juste Álvarez, A. De La Calle Moreno, A. Rodriguez Antolín, J.M. Duarte Ojeda, M. Pamplona Casamayor, Á. Tejido Sánchez, L. García González, A. Arrébola Pajares, J. Rodriguez De La Calle
Journal: European Urology (2022)
Treatment patterns and outcomes in <i>ALK</i> or <i>ROS1</i> altered NSCLC: An ATOMIC Registry Study.
Authors: Melina Elpi Marmarelis, Connor B. Grady, Geoffrey Liu, Devalben Patel, Stephen V. Liu, Gabriela Liliana Bravo Montenegro, Tejas Patil, Jorge J. Nieva, Amanda Herrmann, Kristen Marrone, Vincent K. Lam, Fangdi Sun, Jonathan Dowell, Vamsidhar Velcheti, Matthew Nguyen, Kelsey Leigh Miller, Wade Thomas Iams, Wei-Ting Hwang, D. Ross Camidge, Charu Aggarwal
Journal: Journal of Clinical Oncology (2022)

9077 Background: New tyrosine kinase inhibitors (TKIs) targeting ALK and ROS1 alterations in non-small cell lung cancer (NSCLC) have emerged over the last decade. Given the rarity of these genetic changes in NSCLC, data on long term outcomes with sequential therapies are limited. Methods: We conducted a multicenter retrospective cohort study of patients with metastatic NSCLC and ALK or ROS1 alterations across 12 Academic Thoracic Oncology Medical Investigators Consortium (ATOMIC) sites between 1/29/2007 and 3/31/2021. Data were abstracted from the electronic medical record. Median time to treatment discontinuation (TTD) of 1st TKI, overall survival (OS), and time to brain metastases were estimated using Kaplan-Meier methodology from start date of 1st TKI. Results: 566 patients with ALK (n = 464) or ROS1 (n = 102) were included. The majority (ALK: 426/464, 92%; ROS1: 88/102, 86%) received a TKI at some point during therapy (1 st line TKI n = 262 ALK, 48 ROS1). Crizotinib was the most common 1 st TKI (ALK: 57%; ROS1: 88%). Following crizotinib, alectinib (64%) and lorlatinib (41%) were the most common subsequent TKIs for ALK and ROS1, respectively. Alectinib (38%) and entrectinib (10.2%) were the 2 nd most common initial TKIs used in ALK and ROS1, respectively. Additional treatment patterns presented in table. With a median follow up time of 31.1 (ALK, 95% CI, 27.6-35.0) and 32.6 (ROS1, 95% CI, 25.7-39.6) months, median OS from start of 1 st TKI was 53.3 (ALK, 95% CI, 40.0-68.9) and 42.0 (ROS1, 95% CI, 31.8-NA) months. Out of the 321 patients with brain imaging prior to 1st line therapy, 40% (105/262, ALK) and 39% (23/59, ROS1) had CNS disease. Median time to development of brain metastases from start of 1 st TKI in those without previous CNS disease (ALK: 278; ROS1: 58) was 30.0 (ALK, 95% CI, 25.3-39.1) and 27.0 (ROS1, 95% CI, 18.2-NA) months. Median TTD of 1 st TKI was 11.2 (ALK) and 10.8 (ROS1) months. Conclusions: This is the largest retrospective cohort of NSCLC patients with ALK or ROS1 rearrangements treated in the real world setting. CNS metastases are common and subset analyses by agent and by year of diagnosis will be presented. Median time to CNS metastasis of &gt; 2 years supports revision of the NCCN guidelines to include regular surveillance brain MRIs in this population. [Table: see text]
Lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma: A large real-world study from two centers.
Authors: Xu Yang, Bowen Chen, Yanyu Wang, Yunchao Wang, Junyu Long, Nan Zhang, Jinnan Xue, Ziyu Xun, Linzhi Zhang, Jiamin Cheng, Jin Lei, Jie Pan, Ke Hu, Mei Guan, Li Huo, Yilei Mao, Xinting Sang, Yinying Lu, Hai-Tao Zhao
Journal: Journal of Clinical Oncology (2022)

e16155 Background: Combining lenvatinib (a multikinase inhibitor) with programmed cell death protein-1 (PD-1) inhibitor has been explored in Unresectable hepatocellular carcinoma (uHCC) in phase 1b trials. This study aimed to investigate the real-word efficacy and safety of lenvatinib plus PD-1 inhibitor for large Chinese patients uHCC cohorts. Methods: BCLC stage B or C uHCC patients were included. Data was collected from Oct 2017 to Nov 2021 retrospectively. Patients were treated with lenvatinib and PD-1 inhibitor (pembrolizumab or nivolumab or camrelizumab or sintilimab or toripalimab or tislelizumab). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and objective response rate (ORR) evaluated by RECIST v1.1 criteria. Adverse events (AEs) were assessed using CTCAE v5.0. Prognostic factors of survival were also analyzed. Results: 378 uHCC patients of BCLC stage B (12.7%) and C (87.3%) from two medical centers were included in China. The median age was 55 (range 18-89) years and 86.5% patients were male. ECOG scores were 0 (43.7%), 1 (43.4%) and 2 (13.0%), while Child-pugh grade were A (77.5%) and B (22.5%) respectively. The median OS was 17.8 (95% CI 14.0-21.6) months. The median PFS was 6.9 (95% CI 6.0-7.9) months. The best objective response rate (ORR) and disease control rate (DCR) was 74/378 (19.6%) and 278/378 (73.5%) respectively. Child-pugh grade (A vs. B), ECOG score (0 vs. 1-2), BCLC stage (B vs. C) and achieve response (yes vs. no) were the prognostic factors for both OS and PFS. All (100%) experienced all-grade adverse events (AE). The most frequent AEs were fatigue, diarrhea, hypertension, decreased appetite. The most common ≥Grade 3 AEs were hypertension (13.2%), fatigue (7.1%), decreased platelet count (6.3%), increased blood bilirubin (6.1%), diarrhea (6.1%) and gastrointestinal hemorrhage (4.8%). Conclusions: This real-world study of lenvatinib plus PD-1 inhibitors achieved long survival and considerable ORR for uHCC patients in China. The tolerability of combination therapy was acceptable but should be still monitored closely. Clinical trial information: NCT03892577. [Table: see text]
Tumor mutation burden (TMB) and <i>Notch1</i> gene alteration are associated with short disease-free survival in early laryngocarcinoma.
Authors: Xi Chen, Xiao-yang Gong, Hai-bing Chen, Dong-sheng Chen, Lele Zhao
Journal: Journal of Clinical Oncology (2022)

e18049 Background: Patients with early-stage laryngocarcinoma, even stage T1-2N0, are at substantial risk of relapse and death. Molecular alterations are thought to be associated with the immune microenvironment in the tumor and to have an important role in predicting the prognosis. In this study, we explored the distinct features of molecular alterations and immune-related gene expression and examined the relationship between molecular alterations and prognosis. Methods: A total of 42 stage T1-2N0 laryngocarcinoma patients were enrolled, no patients received chemotherapy or immunotherapy before surgery, tissue samples from radical operation were collected. Of these, 23 cases developed disease progression within 24 months after operation [shorter disease-free survival (shorter DFS)], while others 19 cases showed longer DFS over 24 months (longer DFS). Distinct features of molecular alterations and immune-related gene expression in Formalin-fixed paraffin-embedded (FFPE) samples through using DNA sequencing and an immune oncology panel RNA sequencing platform were performed. Results: A total of 293 mutations were detected within 42 patients, the median number of mutations in the short-DFS group was higher than that in the long-DFS group (9.0 vs. 5.2; P = 0.045). No correlation between mutation type and DFS was found. TMB-high (Top 25%) was associated with worse DFS (TMB-L: Not reached, TMB-H: 11.5 months, p = 0.036; HR, 2.4; 95% CI 1.05 to 5.48). Among 522 cancer-related genes, alterations in 51 genes were detected. TP53 (33/42, 79%) was the most common mutation gene in the entire cohort. Mutations of LRP1B (30.4% vs 5.3%, p = 0.039) and Notch1 (21.7% vs 0%, p = 0.030) were significantly occurred in the short-DFS group, patients with Notch1 mutation had a significantly shorter DFS period (P = 0.0012). Univariate and multivariate analysis showed that high TMB and Notch1 mutation were independent prognostic factors in DFS. Conclusions: In early-stage laryngocarcinoma, Notch1 mutation and high TMB were associated in patients with short-DFS, indicating the potential prognostic biomarkers and therapeutic molecular targets for early-stage laryngocarcinoma.
Mitochondrial therapy can inhibit melanoma development.
Authors: Elena M. Frantsiyants, Irina V. Neskubina, Alla I. Shikhlyarova, Natalia D. Cheryarina, Ekaterina I. Surikova, Valeria A. Bandovkina, Ludmila A. Nemashkalova, Irina V. Kaplieva, Lidia K. Trepitaki, Polina S. Kachesova, Ludmila P. Kuchkina, Viktoriya L. Volkova, Marina A. Engibaryan, Yulia V. Ulianova, Oleg I. Kit
Journal: Journal of Clinical Oncology (2022)

e21571 Background: Mitochondria of tumor cells undergo adaptive changes for even more active reproduction of tumor cells in the acidic and hypoxic microenvironment of tumor tissue. The purpose of this study was to evaluate antitumor effect of mitochondrial therapy in BALB/c Nude mice of both genders with B16/F10 melanoma growth. Methods: Male (n = 10) and female (n = 10) BALB/c Nude mice were injected subcutaneously with 0.5 ml of a suspension of B16/F10 mouse melanoma tumor cells in saline at a dilution of 1:20. Mitochondria (MC) were isolated from rat liver. 24 hours after subcutaneous transplantation of B16/F10 melanoma, mice were intraperitoneally injected with freshly isolated mitochondria (3.3 mg of protein per animal in 0.3 ml of saline). Further, mitochondrial therapy (MC therapy) was carried out according to the scheme on days 3, 5, 9, 13, 16, 19, 21. Male BALB/c Nude mice with subcutaneous inoculation of B16/F10 melanoma receiving intraperitoneal injections with 0.3 ml of saline served as controls. Results: Subcutaneous tumors in mice of both genders could be determined on the 5th day from the moment of tumor transplantation. In males, the regressive effect of MC therapy was recorded from the 8th day of tumor growth. The average tumor volume in males with MC therapy on day 8 was 3.0 times less than in the control group. On days 12 and 15, the regressive difference in tumor volumes between the groups was 1.8 times (p &lt; 0.05) (MC therapy). On day 19, a slower tumor growth was recorded in the group with MC therapy, where the tumor volume was 2 times lower compared to the control volumes. At the end of the experiment on day 22, the difference in the average tumor volumes was 3.2 times, i.e. a significant inhibition of tumor growth was determined in males treated with MC therapy. A sizeable tumor node in females treated with MC therapy formed longer than in males, remaining as a flat tumor spot for up to 8 days. The inhibition of the growth of a large tumor node was determined on day 12 of melanoma growth, and the difference with the control values was 1.8 times (p &lt; 0.05). On day 15, the tumor volumes in females with MC therapy decreased by 2.2 times compared with the control values, on day 19 - by 2.1 times. As a result, by the end of the experiment (day 22), the difference with the control group was 2.7 times. Conclusions: MC therapy inhibits the growth of B16/F10 melanoma in male and female BALB/c Nude mice. Formation of a sizeable tumor node and the start the tumor growth inhibition differs in time depending on the gender of experimental animals.
Identification of pathologic factors associated with intraoperative positive surgical margins at NeuroSAFE for clinical decision-making on nerve-sparing surgery
Authors: M.A. van der Slot, A. Den Bakker, M. Busstra, M. Gan, O.S. Klaver, J.B.W. Rietbergen, S. Remmers, C. Kweldam, C.H. Bangma, M.J. Roobol, G.J.L.H. Van Leenders
Journal: European Urology (2022)